This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The p90 kDa ribosomal S6 kinase 2 (RSK2) belongs to the mitogen-activated protein kinase signaling pathway and regulates diverse cellular processes such as cell growth and differentiation, as well as cell survival and proliferation. RSK2 is overexpressed in human prostate cancer, breast cancer, lung, colon and skin cancer. RSK2 is associated with osteosarcoma development, and knockdown of RSK2 effectively induces apoptosis in human myeloma cells. RSK2 is unique dual kinase, which is characterized by the presence of two distinct functional kinase domains in one polypeptide. The three-dimensional structures of full length RSK2 has not been determined to date, and the precise mechanisms of its activation remain elusive. Lack of such knowledge impedes development of their selective inhibitors needed for treatment of cancers. The focus of the project is to resolve crystals structure of full length RSK2 and/or its separate kinase domains. The objective is to define structure-function relationship between the two kinase domains using a crystallographic approach. The hypothesis is that the N-terminal kinase domain of RSK2 adopts a unique kinase conformation. The extracellular signal- regulated kinase 2 (ERK2) is up-stream activating kinase of RSK2, that binds to the C-terminal RSK2 and phosphorylates it.